Acamprosate (calcium bis acetyl-homotaurine), is a synthetic analog of γ-amino butyric acid (GABA) and is used as an adjunct for treatment of alcohol dependence. Alcohol dependence is a chronic relapsing medical disorder which bears many of the characteristics of other medical relapsing disorders such as diabetes and hypertension. Without pharmacological treatment to accompany psychotherapy, up to 70% of patients resume drinking within one year (see Bankole et al., Biochem Pharmacol., 2008, 75:34-56).
As alcohol inhibits the activity of N-methyl-D-aspartate receptors (NMDARs), chronic alcohol consumption leads to the upregulation of these receptors. Sudden alcohol abstinence results in excessive activation of NMDARs, leading to symptoms such as delirium tremens and excitotoxic neuronal death (Tsai et al., Ann Rev Med, 1998, 155:726-732; Tsai et al., Am J Psych, 1998, 155:726-732). Acamprosate reduces this effect in vivo. Studies have also suggested that acamprosate protects cultured cells in excitotoxicity induced by ethanol withdrawal, and by glutamate exposure combined with ethanol withdrawal.
Absorption of acamprosate following oral administration occurs via both passive diffusion through the intestinal epithelium and active uptake via amino acid transporter that are expressed in the small intestine (Mas-Serrano et al., Alcohol & Alcoholism, 2000, 35:324-330). Acamprosate exhibits poor absorption in the intestine after oral dosing. It is thought this is primarily due to poor permeability in the intestinal epithelium. Moreover, the uptake transporter in the small intestine becomes saturated with the current dosage form at the dose of 2×333 mg, equivalent to 600 mg of acamprosate free acid, three times daily. Poor absorption not only reduces therapeutic effectiveness of an acamprosate oral dosage form, but also unabsorbed drug passes to the lower GI, resulting in adverse side effects such as diarrhea. Some of these and other side effects are related to the large amounts of calcium, and replacement or elimination of calcium with other cations, e.g., magnesium or sodium, may be beneficial.
Accordingly, it would be useful to manufacture an oral dosage form which is able to provide prolonged and steady levels of acamprosate to the small intestine at concentrations which allow optimal uptake by the intestinal transporter and an effectively longer time for intestinal absorption.
Gastric retained forms that can form the basis for the sustained release of a drug have been previously described, for example, in Gusler et al. (U.S. Pat. No. 6,723,340), Berner et al. (U.S. Pat. No. 6,488,962), Shell et al., (U.S. Pat. No. 6,340,475) and Shell et al. (U.S. Pat. No. 6,635,280). These formulations make use of one or more hydrophilic polymers which swell upon intake of water from gastric fluid. Thus, when administered in the fed mode, when the diameter of the pyloric sphincter is contracted and reduced, the dosage form will swell to a size to be retained in the stomach for a minimum of four hours or more. These formulations may be designed to produce desired release and delivery profiles for both highly soluble and poorly soluble drugs.
As presently disclosed, gastric retentive dosage forms are formulated specifically to provide extended release of acamprosate or of a salt or prodrug of acetyl homotaurine from the stomach into the upper gastrointestinal tract, resulting in prolonged exposure and lower but steady release rate of the acamprosate or related salt or prodrug to the small intestine to optimize uptake and enhance bioavailability. These gastric retentive dosage forms are proposed to be administered with a meal. Gastric retentive dosage forms are generally applicable to drugs where the bioavailability improves when administered with a meal. Since the AUC and Cmax of the current acamprosate dosage form decrease by 23% and 42%, respectively, when administered with food instead of fasting, it is surprising that acamprosate can be administered with good bioavailability from a gastric retentive dosage form that depends on administration in the fed mode.